Chronic hepatitis B (CH-B) is common in HIV-infected persons, and HIV accelerates the rate of hepatitis B-related liver disease progression. In the Multicenter AIDS Cohort Study (MACS), the risk of liver-related death was nearly 18 times higher in those coinfected with HIV-HBV compared to those with CH-B alone. Furthermore, the rate was two times higher after compared to before 1996, the time of the introduction of highly active antiretroviral therapy (HAART). These data support the need to study the effects of HAART on liver disease progression in HIV-HBV coinfected persons. This proposal investigates CH-B in HIV-infected persons receiving HAART in a cohort of HIV-HBV coinfected patients from the MACS and two well-characterized Australian cohorts, one in Melbourne and one in Sydney. The first aim will test the hypothesis that long-term HAART active against HBV will alter the rate of HAART-related hepatotoxicity in HIV-HBV coinfected persons. We will determine the rates of hepatotoxicity over a five-year period following HAART initiation. In the second aim the magnitude and durability of HBV DNA suppression with a HBV active HAART regimen will be determined by prospectively following HBV DNA levels. The third aim is designed to study the evolution of resistance mutations that occur in persons who do not have a durable suppression of their HBV DNA with HBV-active HAART. The entire HBV genome will be sequenced at the time of relapse and then followed subsequently for the development of compensatory mutations. These mutant viruses will be tested for anti-viral drug sensitivity and replication competence. These aims are integrated in the fourth aim, which tests the hypothesis that an effective HBV active HAART regimen will slow the rate of liver disease progression. In this aim, paired liver biopsies will be examined to determine the rates of liver disease progression and analyzed with respect to the ability to maintain a durable HBV DNA response, to the development of drug-resistant mutants, and to intrahepatic levels of HBV DNA and ccc DNA. Given the experience of the investigative team and the well-characterized cohorts involved, the results from this proposal will yield insights into the management of HIV-HBV co-infected patients.